Pharmacokinetic and toxicity study of intravitreal erythropoietin in rabbits.
OBJECTIVE
To study the pharmacokinetics and toxicity of intravitreal erythropoietin (EPO) for potential clinical use.


METHODS
For toxicity study, 4 groups (60 rabbits) with intravitreal injection (IVit) of EPO were studied (10 U, 100 U, or 1,000 U) per eye for single injection and 0.6 U/eye (the designed therapeutic level in rabbits) for monthly injections (6X). Eye examination, flash electroretinogram (ERG), and fluorescein angiography (FA) were carried out before and after injection. The rabbits were killed for histological study at different intervals. For the pharmacokinetic study, after IVit of 5 U EPO into left eyes, 44 rabbits were killed at different intervals, and the EPO levels in vitreous, aqueous, retina and serum were analyzed by enzyme-linked immunosorbent assay.


RESULTS
At all of the time points examined, the eyes were within normal limits. No significant ERG or FA change was observed. The histology of retina remained unchanged. The pharmacokinetic profile of EPO in ocular compartments was summarized as follows. The half-life times of EPO in vitreous, aqueous and serum were 2.84, 3.24 and 2.12 d, respectively; and Cmax were 4615.75, 294.31 and 1.60 U/L, respectively. EPO concentrations in the retina of the injected eye peaked at 1.36 U/g protein at 6 h following injection, with the half-life observed to be 3.42 d.


CONCLUSIONS
IVit of EPO in a wide range is well tolerated and safe for rabbit eyes. At doses up to 10-fold higher than therapeutic levels, EPO has a pharmacokinetic profile with faster clearance, which is favorable for episodic IVit.
Zhang
Jing-fa
JF
Laboratory of Clinical Visual Sciences, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai JiaoTong University School of Medicine, Shanghai 200025, China.
Wu
Ya-lan
YL
Xu
Jing-ying
JY
Ye
Wen
W
Zhang
Yu
Y
Weng
Huan
H
Shi
Wo-dong
WD
Xu
Guo-xu
GX
Lu
Luo
L
Dai
Wei
W
Sinclair
Stephen H
SH
Li
Wei-ye
WY
Xu
Guo-tong
GT
D000818:Animals; D002452:Cell Count; D004596:Electroretinography; D004921:Erythropoietin / Q000493:pharmacokinetics* / Q000633:toxicity*; D006801:Humans; D008297:Male; D008845:Microinjections; D011817:Rabbits; D011994:Recombinant Proteins; D012160:Retina / Q000166:cytology / Q000378:metabolism; D014822:Vitreous Body / Q000473:pathology / Q000502:physiology*
D011994:Recombinant Proteins; D004921:Erythropoietin